Stabilization of multivitamin/trace elements formulations

ABSTRACT

Disclosed are aqueous multivitamin/trace elements formulations stabilized by a water soluble, organic acid that contains carbon-to-carbon unsaturation and water soluble salts thereof selected from the group consisting of maleic acid, fumaric acid, maleamic acid and acrylic acid.

This application is a continuation-in-part of application Ser. No. 866,842, filed May 27, 1986 issued on Apr. 26, 1988 as U.S. Pat. No. 4,740,373.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to a method of stabilizing aqueous parenteral solutions of multivitamins in the presence of trace elements and compositions produced thereby for human and veterinary administration.

As is well known, in addition to the various basic nutritive materials which are required by humans and animals, a variety of other nutrients and essential elements are also required for the maintenance of good health. The present invention is directed to nutrients and essential elements, sometimes called "micronutrients", from which relatively very small amounts are needed to provide a well-balanced, healthy diet. For convenience, the compositions of the invention will be described as relate to humans, however, the same can as well be used for veterinary purposes. While the compositions of the invention may be used as regular supplements to nutrients obtained through the digestive system, it especially concerns total parenteral nutrition to provide nutritional support for persons unable to meet their nutritional requirements through the digestive system, i.e. for nutritional rehabilitation of patients.

Total parenteral nutrition (TPN) has been used for many years and an expanded knowledge of nutritional requirements led to the development of a wide array of products from which the TPN solutions can be formulated. The Nutritional Advisory Group of the American Medical Association (AMA) has developed recommendations for the parenteral use of multivitamin preparations. The guidelines for adult formulations are as follows (JPEN 3: 258-262, 1979)

    ______________________________________                                                              Daily                                                     Vitamin              Administration                                            ______________________________________                                         A                    3,300   IU                                                D                    200     IU                                                E                    10      IU                                                Ascorbic Acid        100     mg                                                Folacin              400     mcg                                               Niacin               40      mg                                                Riboflavin           3.6     mg                                                Thiamin              3       mg                                                Pyridoxine (B6)      4       mg                                                Cyanocobalamin (B12) 5       mcg                                               Pantothenic Acid     15      mg                                                Biotin               60      mcg                                               ______________________________________                                    

The medical profession has focused increasing attention on the importance of trace elements in the nutritional management of medical, surgical, and traumatic conditions. The AMA has also published guidelines for trace element preparations for parenteral use (JPEN 3: 263-267, 1979):

    ______________________________________                                                             Daily                                                      Trace Elements      Administration                                             ______________________________________                                         Zinc                2.5-4    mg                                                Copper              0.5-1.5  mg                                                Chromium            10-15    mcg                                               Manganese           0.15-0.8 mg                                                ______________________________________                                    

The AMA did not address other trace elements, however, there are increasing data for the role of these various trace elements in good nutritional support. It is generally known that the "essential elements", i.e. calcium, magnesium, sodium and potassium, furthermore zinc, manganese, copper, cobalt, chromium, iron, molybdenum, vanadium, selenium and nickel are indispensable for the normal function of living organisms. The essential elements are the constituents or activators of numerous enzyme systems, they are in close correlation with the level of certain vitamins in the organism and with the function of the hormone system. The deficiency of essential elements greatly suppresses the biosynthesis of proteins, enzymes, hormones and other biologically active substances required to control the normal functions of the living organism as a whole.

The JPEN 5: 424-429, 1981 reports on health disorders associated with the insufficiency of some essential trace elements in TPN: Zinc deficiency manifests in a variety of diseases including acrodermatitic skin lesions, impaired immunity, poor growth, impaired wound healing, and mental disturbances; copper deficiency results in hematologic abnormalities, usually anemia with leukopenia and neutropenia; chromium deficiency has been recognized to play a role in glucose intolerance, weight loss, peripheral neuropathy or encephalopathy; and selenium deficiency in experimental animals was observed to cause liver necrosis, pancreatic atrophy, and muscular dystrophy. Manganese is an actuator of several enzymes being involved in protein synthesis and function of the central nervous system. It is essential for bone structure and reproduction.

2. Description of the Prior Art

In general, liquid multivitamin preparations of the prior art are packaged in two separate vials or syringes, or double compartment vials or syringes to prevent interaction between some of the vitamins. Such interaction results in discoloration of the solution and loss of potency. Another approach to solve the interaction problem resulted in lyophilizing multivitamin preparations and reconstituting the same just prior to injection.

The ingredients interaction problem is even more serious when, in addition to containing multivitamins, the preparation also contains trace elements, especially copper. To circumvent the problem, the prior art, again, provided a two or three package system, one or two of which contained the multivitamin and one the trace elements. The contents of the packages were either separately infused into the patient or were admixed just prior to infusion. While the former method is undesirably cumbersome, the latter method is unsatisfactory for the reason that the reactions between the trace elements and the multivitamins are so rapid that the browning reaction and turbidity can be observed within minutes of admixing the two phases. In addition, the interaction could cause clogging of the infusion needle and the introduction of solid particles into the vein of the patient. This problem could be especially serious with infusions mixed several hours prior to addition to TPN solutions.

The present invention is designed to solve the above-described problems and to provide multivitamin/trace elements formulations in aqueous solution for parenteral administration to patients.

SUMMARY OF THE INVENTION

It is a main object of the present invention to administer to patients multivitamins and trace elements together as one entity in an infusion mixture. Heretofore such administration was not possible due to the instantaneous reaction of trace elements with several of the vitamins forming darkly colored, turbid solutions with heavy precipitation occurring within minutes. Examples of such undesirable reactions include reaction of copper with vitamin C, riboflavin, folic acid and vitamin B₁₂.

It is another object of the present invention to provide a multivitamin/trace elements formulation which is stable for at least 4 to 8 hours at room temperature or 8 to 12 hours refrigerated so as to allow normal manipulative time in hospital infusion.

It has been surprisingly discovered that the rapid inter-reactions between vitamins and trace elements can be prevented by the use of a water soluble, organic acid that contains carbon-to-carbon unsaturation and water soluble salts thereof. Such organic acids include: maleic acid, fumaric acid, maleamic acid and acrylic acid. Water soluble saturated weak organic acids, such as citric acid, acetic acid, tartaric acid, gluconic acid, succinic acid, lactic acid, and oxalic acid showed no stabilizing effects. Cyanoacetic acid which has an unsaturated carbon to nitrogen bond was also ineffective in stabilizing the multivitamin/trace elements formulations.

In accordance with this discovery, several embodiments of the invention are provided as will be described hereunder.

a. One embodiment of the present invention lies in an injectable, two compartment, one unit vial or syringe, aqueous liquid-liquid preparation of multivitamins/trace elements maintained separately, one of the two compartments, in addition to containing the active ingredients, contains a sufficient amount of a water soluble organic acid having carbon-to-carbon unsaturation to stabilize the injectable combination preparation.

b. Still another embodiment of the present invention is the same as that described in (a) except the container is a two-unit vial or syringe package.

c. A further embodiment of the present invention provides for lyophilization of the respective solution or solutions referred to in (a) and (b) which are reconstituted prior to infusion.

The stabilizer can be added separately or combined with either multivitamins or trace elements.

The various embodiments of the present invention are useful for adult, pediatric, neonatal or TPN regimen and also for veterinary application.

It has been found that a molar ratio of 3 to 30 times of stablizer to combined trace elements is necessary to effectively stabilize either the multivitamin or the trace elements containing solution which corresponds to about 0.5 to 5.0% w/v of stabilizer in the solution. The preferred method of stabilization is the use of 5 to 10 molar ratio of the water soluble unsaturated organic acid in the trace elements solution. While the mechanism of stabilization is not understood, it is postulated that stabilization is due to weak bonding of the trace element(s) to the unsturated carbon-carbon (double) bond.

DETAILED DESCRIPTION OF THE INVENTION

In general, the multivitamin/trace elements formulations of the present invention are directed by therapeutic considerations based on judgements of those skilled in the art of nutrition. For special deficiencies additional components or amounts may be added. Tables I and II show the amounts of the various vitamins and trace elements considered advantageous for use in TPN formulations.

                  TABLE I                                                          ______________________________________                                         Vitamin Range                                                                                         Broad      Preferred                                    Active   Forms         Range      Range*                                       ______________________________________                                         Vitamin A,                                                                              alcohol,        230-10,000                                                                              3,300-5,000                                  IU       palmitate,                                                                     acetate                                                               Vitamin B.sub.1,                                                                        hydrochloride,                                                                               0.05-45.0  3.0-6.0                                      mg       mononitrate,                                                                   phosphate                                                                      esters                                                                Vitamin B.sub.2,                                                                        riboflavin,   0.07-10.0  3.0.6.0                                      mg       riboflavin-5-                                                                  phosphate                                                                      sodium salt                                                           Vitamin B.sub.6,                                                                        hydrochloride 0.04-12.0  4.0-6.0                                      mg                                                                             Vitamin C,                                                                              Vitamin C,       4-1,000 100-200                                      mg       sodium                                                                         ascorbate                                                             Vitamin D,                                                                              ergocal-        44-1,000 200-400                                      IU       ciferol,                                                                       calciferol                                                            Vitamin E,                                                                              d or dl       0.66-10     5-10                                        IU       tocopheryl,                                                                    d or dl tocopheryl                                                             acetate                                                               Niacinamide,                                                                            niacinamide,  0.25-100   40-60                                        mg       niacin                                                                Pantothenic                                                                             d-panthenol,  0.3-25     10-15                                        Acid, mg calcium                                                                        pantothenate                                                          Vitamin K,                                                                              phytonadione, 0.04-1.0   0.10-0.5                                     mg       menadiole,                                                                     menadione                                                                      bisulfite,                                                                     menadiol                                                                       phosphate                                                             Biotin, mcg                                                                             biotin         10-100    25-60                                        Folic Acid,                                                                             folic acid,    5-800     400-600                                      mcg      sodium                                                                         folate                                                                Vitamin B.sub.12,                                                                       cyanoco-      0.04-10    2-5                                          mcg      balamin,                                                                       cobalamin,                                                                     hydroxy                                                                        cobalamin                                                             ______________________________________                                          *Preferred Range for adult formula                                       

                  TABLE II                                                         ______________________________________                                         Trace Element Range                                                                                Broad       Preferred                                      Active  Forms       Range       Range*                                         ______________________________________                                         Zinc    chloride,                                                                               100    mcg-10 mg 3-6    mg                                            sulfate                                                                        acetate,                                                                       citrate,                                                                       lactate,                                                                       nitrate,                                                                       tartrate                                                               Copper  chloride,                                                                               20     mcg-2.8 mg                                                                               0.4-1.5                                                                               mg                                            sulfate,                                                                       acetate,                                                                       nitrate,                                                                       gluconate                                                              Manganese                                                                              chloride,                                                                               2      mcg-2.5 mg                                                                               0.15-0.80                                                                             mg                                            sulfate                                                                        acetate,                                                                       nitrate                                                                Chromium                                                                               chloride,                                                                               0.14   mcg-20 mcg                                                                               10-15  mcg                                           sulfate,                                                                       acetate,                                                                       nitrate                                                                ______________________________________                                          *Preferred Range for adult formula                                       

In addition to the active ingredients of vitamins and trace elements, excipients conventionally used in infusable solutions can be used, illustrative examples and amounts of which are shown in Table III.

                  TABLE III                                                        ______________________________________                                         Excipients                                                                     ______________________________________                                         Antioxidants and                                                                              thiourea, thioglycerol, thio-                                   Stabilizers    sorbitol, cysteine, glycine,                                    (0.005-2.0% w/v)                                                                              sodium formaldehyde sulfoxylate,                                               butylated hydroxyanisole, butyl-                                               ated hydroxytoluene, nordihydro-                                               gluaiaretic acid, ethyl hydro-                                                 caffeate, gentistic acid ethonal-                                              amide, propyl gallate, ascorbyl                                                palmitate, iron salts.                                          Solvents       propylene glycol, glycerin,                                     (0.01 to 30% v/v)                                                                             alcohol, polyethylene glycol.                                   Solubilizers   polyoxylated sorbitol fatty acid                                (0.01 to 5% w/v)                                                                              esters, polyoxylated vegetable                                                 oils.                                                           Preservatives  (for multidose units) parabens,                                 (0.01 to 1.0% w/v)                                                                            chlorobutanol, phenol, benzyl                                                  alcohol.                                                        ______________________________________                                    

The multivitamin/trace elements formulations of the present invention may be prepared using commercially available ingredients by methods well-known in the prior art. (Suppliers of raw materials include Hoffman-LaRoche Co., R. W. Greef & Co., H. Reisman Corp., Roussel Corp. and Rhone Poulenc Inc.)

The following examples will illustrate formulations according to the present invention.

EXAMPLE 1 (Adult)

Ten grams of maleic acid is dissolved in 900 mL of water for injection. To this is added

    ______________________________________                                         0.536    g         copper chloride (2H.sub.2 O)                                1.68     g         zinc chloride                                               0.364    g         manganese chloride (4H.sub.2 O)                             10.25    mg        chromium chloride (6H.sub.2 O)                              ______________________________________                                    

The mixture is stirred until the solution is complete and adjusted to 1 liter volume.

Five mL of this mixture containing

    ______________________________________                                         1.0 mg              copper                                                     4.0 mg              zinc                                                       0.5 mg              manganese                                                   10 mcg             chromium                                                   ______________________________________                                    

is added to a vial of lyophilized or liquid multivitamin solution containing the following vitamins per unit dose:

    ______________________________________                                         3,300      IU          vitamin A                                               200        IU          vitamin D                                               10         IU          vitamin E                                               0.15       mg          vitamin K.sub.1                                         6.0        mg          thiamin                                                 3.6        mg          riboflavin                                              6.0        mg          pyridoxine                                              40         mg          niacinamide                                             60         mcg         biotin                                                  5.0        mcg         vitamin B.sub.12                                        15.0       mg          pantothenic acid                                        600        mcg         folic acid                                              200        mg          ascorbic acid.                                          ______________________________________                                    

EXAMPLE 2 (Adult)

Five grams of fumaric acid is dissolved in 900 mL of water for injection and

    ______________________________________                                         1.18    g         copper sulfate (5H.sub.2 O)                                  3.54    g         zinc sulfate (7H.sub.2 O)                                    0.307   g         manganese sulfate (H.sub.2 O) and                            15.04   mg        chromium sulfate are added and                                                 dissolved.                                                   ______________________________________                                    

The solution is then brought to 1 liter volume. A 5 mL aliquot is taken containing

    ______________________________________                                         1.5        mg           copper                                                 4          mg           zinc                                                   0.5        mg           manganese                                              10         mcg          chromium                                               ______________________________________                                    

and is added to a liquid or lyophilized multivitamin mixture for infusion purposes, the multivitamin mixture containing the following vitamins:

    ______________________________________                                         3,300      IU          vitamin A                                               200        IU          vitamin D                                               10         IU          vitamin E                                               3.0        mg          thiamin                                                 3.6        mg          riboflavin                                              4.0        mg          pyridoxine                                              40         mg          niacinamide                                             60         mcg         biotin                                                  5.0        mcg         vitamin B.sub.12                                        15.0       mg          pantothenic acid                                        400        mcg         folic acid                                              100        mg          ascorbic acid.                                          ______________________________________                                    

EXAMPLE 3 (Adult)

Twenty grams of tris maleate is added to 900 mL of water for injection and stirred to dissolve. Then the following trace elements are added and dissolved:

    ______________________________________                                         0.79     g         copper sulfate (5H.sub.2 O)                                 2.1      g         zinc chloride                                               0.144    g         manganese chloride (4H.sub.2 O)                             10.25    mg        chromium chloride (6H.sub.2 O)                              ______________________________________                                    

The solution is q.s. to 1.0 liter and 5 mL aliquot containing

    ______________________________________                                         1.0        mg           copper                                                 5.0        mg           zinc                                                   0.2        mg           manganese                                              10         mcg          chromium                                               ______________________________________                                    

is mixed with one unit dose of multivitamin solution for infusion delivery. The vitamin concentration is shown in Example 1.

EXAMPLE 4 (Adult)

Twenty five grams of maleic acid is dissolved in 900 mL water for injection and

    ______________________________________                                         1.072    g         copper chloride (2H.sub.2 O),                               2.52     g         zinc chloride                                               0.144    g         manganese chloride (4H.sub.2 O)                             10.25    mg        chromium chloride (6H.sub.2 O)                              ______________________________________                                    

are added and dissolved. The solution is q.s. to 1.0 liter.

Five mL aliquot containing

    ______________________________________                                         2          mg           copper                                                 6          mg           zinc                                                   0.2        mg           manganese                                              10         mcg          chromium                                               ______________________________________                                    

is added to a unit vial of multivitamin or lyophilized multivitamin solution. This is mixed for subsequent addition to the infusion solution. The concentration of vitamins is the same as that shown in Example 1.

EXAMPLE 5 (Adult)

Twenty grams of sodium maleate is dissolved in 900 mL of water for injection. To this is added

    ______________________________________                                         0.5366    g        copper chloride (2H.sub.2 O)                                1.68      g        zinc chloride                                               0.364     g        manganese chloride (4H.sub.2 O)                             10.25     mg       chromium chloride (6H.sub.2 O)                              ______________________________________                                    

The mixture is stirred until the solution is complete and adjusted to 1 liter. Five mL of this mixture, containing the same concentration of trace elements as in Example 1, is added to a unit vial of lyophilized or liquid multivitamins.

The composition of the multivitamin mixture used in this example is

    ______________________________________                                         3,300      IU          vitamin A                                               200        IU          vitamin D                                               10         IU          vitamin E                                               3.0        mg          thiamin                                                 3.6        mg          riboflavin                                              4.0        mg          pyridoxine                                              40         mg          niacinamide                                             60         mcg         biotin                                                  5.0        mcg         vitamin B.sub.12                                        15.0       mg          pantothenic acid                                        400        mcg         folic acid                                              100        mg          ascorbic acid                                           2.5        mg          thiourea.                                               ______________________________________                                    

EXAMPLE 6 (Pediatric)

Five grams of maleic acid is dissolved in 900 mL water for injection and

    ______________________________________                                         0.161   g         copper chloride (2H.sub.2 O)                                 0.63    g         zinc chloride                                                0.072   g         manganese chloride (4H.sub.2 O) and                          2.05    mg        chromium chloride (6H.sub.2 O)                               ______________________________________                                    

are added and dissolved. The solution is brought to 1 liter.

Five mL of this mixture containing

    ______________________________________                                         0.3        mg           copper                                                 1.5        mg           zinc                                                   0.1        mg           manganese                                              2          mcg          chromium                                               ______________________________________                                    

is added to a unit vial of lyophilized or liquid pediatric multivitamin solution. The composition of multivitamin pediatric solution is

    ______________________________________                                         2,300      IU          vitamin A                                               400        IU          vitamin D                                               7          IU          vitamin E                                               0.2        mg          vitamin K.sub.1                                         17         mg          niacinamide                                             1.4        mg          riboflavin                                              1.2        mg          thiamin                                                 1.0        mg          pyridoxine                                              5.0        mg          pantothenic acid                                        80         mg          ascorbic acid                                           20         mcg         biotin                                                  1.0        mcg         vitamin B.sub.12                                        140.0      mcg         folic acid.                                             ______________________________________                                    

EXAMPLE 7 (Neonatal)

2.5 grams of maleic acid is dissolved in 900 mL water for injection and

    ______________________________________                                         0.032   g         copper chloride (4H.sub.2 O)                                 0.25    g         zinc chloride                                                0.014   g         manganese chloride (4H.sub.2 O) and                          0.61    mg        chromium chloride (6H.sub.2 O)                               ______________________________________                                    

are added and dissolved. The solution is q.s. to 1 liter and 5 mL of this mixture containing

    ______________________________________                                         0.06       mg           copper                                                 0.6        mg           zinc                                                   0.02       mg           manganese                                              0.6        mcg          chromium                                               ______________________________________                                    

is added to a unit vial of lyophilized or liquid multivitamin containing the following vitamins:

    ______________________________________                                         1,400      IU          vitamin A                                               200        IU          vitamin D                                               4          IU          vitamin E                                               0.1        mg          vitamin K.sub.1                                         10         mg          niacinamide                                             0.8        mg          riboflavin                                              0.7        mg          thiamin                                                 0.6        mg          pyridoxine                                              3.0        mg          pantothenic acid                                        50         mg          vitamin C                                               12         mcg         biotin                                                  0.6        mcg         vitamin B.sub.12                                        90.0       mcg         folic acid.                                             ______________________________________                                    

EXAMPLE 8 (Adult)

    ______________________________________                                         0.536    g         copper chloride (2 H.sub.2 O)                               1.26     g         zinc chloride                                               0.144    g         manganese chloride (4H.sub.2 O)                             10.25    mg        chromium chloride (6H.sub.2 O)                              ______________________________________                                    

are dissolved in 900 mL water for injection. The solution is adjusted to pH 2 with hydrochloric acid and the volume is brought to 1 liter.

5 mL of this mixture containing

    ______________________________________                                         1.0        mg           copper                                                 3.0        mg           zinc                                                   0.2        mg           manganese                                              10         mcg          chromium                                               ______________________________________                                    

is added to a unit vial of lyophilized or liquid multivitamins containing the following vitamins:

    ______________________________________                                         3,300     IU           vitamin A                                               200       IU           vitamin D                                               10        IU           vitamin E                                               0.15      mg           vitamin K.sub.1                                         6.0       mg           thiamin                                                 3.6       mg           riboflavin                                              6.0       mg           pyridoxine                                              40        mg           niacinamide                                             60        mcg          biotin                                                  5.0       mcg          vitamin B.sub.12                                        15.0      mg           pantothenic acid                                        600       mcg          folic acid                                              200       mg           ascorbic acid                                           1%        w/v          maleic acid                                             0.3       mg           iron peptonate                                          1.0       mg           disodium edetate.                                       ______________________________________                                    

EXAMPLE 9 (Adult)

Ten grams of maleamic acid is dissolved in 900 mL of water for injection. To this is added

    ______________________________________                                         0.536    g         copper chloride (2H.sub.2 O)                                1.68     g         zinc chloride                                               0.364    g         manganese chloride (4H.sub.2 O)                             10.25    mg        chromium chloride (6H.sub.2 O)                              ______________________________________                                    

The mixture is stirred until the solution is complete and adjusted to 1 liter volume.

Five mL of this mixture containing

    ______________________________________                                         1.0        mg           copper                                                 4.0        mg           zinc                                                   0.5        mg           manganese                                              10         mcg          chromium                                               ______________________________________                                    

is added to a vial of lyophilized or liquid multivitamin solution containing the following vitamins per unit dose:

    ______________________________________                                         3,300      IU          vitamin A                                               200        IU          vitamin D                                               10         IU          vitamin E                                               0.15       mg          vitamin K.sub.1                                         6.0        mg          thiamin                                                 3.6        mg          riboflavin                                              6.0        mg          pyridoxine                                              40         mg          niacinamide                                             60         mcg         biotin                                                  5.0        mcg         vitamin B.sub.12                                        15.0       mg          pantothenic acid                                        600        mcg         folic acid                                              200        mg          ascorbic acid.                                          ______________________________________                                    

EXAMPLE 10 (Adult)

Twenty five grams of maleamic acid is dissolved in 900 mL water or injection and

    ______________________________________                                         1.072    g         copper chloride (2H.sub.2 O),                               2.52     g         zinc chloride                                               0.144    g         manganese chloride (4H.sub.2 O)                             10.25    mg        chromium chloride (6H.sub.2 O)                              ______________________________________                                    

are added and dissolved. The solution is q.s. to 1.0 liter.

Five mL aliquot containing

    ______________________________________                                         2          mg           copper                                                 6          mg           zinc                                                   0.2        mg           manganese                                              10         mcg          chromium                                               ______________________________________                                    

is added to a unit vial of multivitamin or lyophilized multivitamin solution. This is mixed for subsequent addition to the infusion solution. The concentration of vitamins is the same as that shown in Example 9.

EXAMPLE 11 (Adult)

Five grams of acrylic acid is added to 900 mL of water for injection and stirred to dissolve. Then the following trace elements are added and dissolved:

    ______________________________________                                         0.79    g         copper sulfate (5H.sub.2 O)                                  2.1     g         zinc chloride                                                0.144   g         manganese chloride (4H.sub.2 O) and                          10.25   mg        chromium chloride (6H.sub.2 O).                              ______________________________________                                    

The solution is q.s. to 1.0 liter and 5 mL aliquot containing

    ______________________________________                                         1.0        mg           copper                                                 5          mg           zinc                                                   0.2        mg           manganese                                              10         mcg          chromium                                               ______________________________________                                    

is mixed with one unit dose of multivitamin solution for infusion delivery. The vitamin concentration is shown in Example 9.

EXAMPLE 12 (Adult)

Seven grams of acrylamide is dissolved in 900 mL water or injection and

    ______________________________________                                         1.072    g         copper chloride (2H.sub.2 O),                               2.52     g         zinc chloride                                               0.144    g         manganese chloride (4H.sub.2 O)                             10.25    mg        chromium chloride (6H.sub.2 O)                              ______________________________________                                    

are added and dissolved. The solution is q.s. to 1.0 liter.

Five mL aliquot containing

    ______________________________________                                         2          mg           copper                                                 6          mg           zinc                                                   0.2        mg           manganese                                              10         mcg          chromium                                               ______________________________________                                    

is added to a unit vial of multivitamin or lyophilized multivitamin solution. This is mixed for subsequent addition to the infusion solution. The concentration of vitamins is the same as that shown in Example 9.

EXAMPLE 13 (Adult)

Seven grams of fumaric acide disodium salt is dissolved in 900 mL of water for injection and

    ______________________________________                                         1.18    g         copper sulfate (5H.sub.2 O)                                  3.54    g         zinc sulfate (7H.sub.2 O)                                    0.307   g         manganese sulfate (H.sub.2 O) and                            15.04   mg        chromium sulfate are added and                               ______________________________________                                    

dissolved. The solution is then brought to 1 liter volume. A 5 mL aliquot is taken containing

    ______________________________________                                         1.5        mg           copper                                                 4          mg           zinc                                                   0.5        mg           manganese                                              10         mcg          chromium                                               ______________________________________                                    

and is added to a liquid or lyophilized multivitamin mixture for infusion purposes, the multivitamin mixture containing the following vitamins:

    ______________________________________                                         3,300      IU          vitamin A                                               200        IU          vitamin D                                               10         IU          vitamin E                                               3.0        mg          thiamin                                                 3.6        mg          riboflavin                                              4.0        mg          pyridoxine                                              40         mg          niacinamide                                             60         mcg         biotin                                                  5.0        mcg         vitamin B.sub.12                                        15.0       mg          pantothenic acid                                        400        mcg         folic acid                                              100        mg          ascorbic acid.                                          ______________________________________                                    

EXAMPLE 14 (Pediatric)

Six grams of fumaric acid disodium salt is dissolved in 900 mL water for injection and

    ______________________________________                                         0.161    g        copper chloride (2H.sub.2 O)                                 0.63     g        zinc chloride                                                0.072    g        manganese chloride (4H.sub.2 O) and                          2.05     mg       chromium chloride (6H.sub.2 O)                               ______________________________________                                          are added and dissolved. The solution is brought to 1 liter.

Five mL of this mixture containing

    ______________________________________                                                0.3 mg           copper                                                        1.5 mg           zinc                                                          0.1 mg           manganese                                                     2   mcg          chromium                                               ______________________________________                                    

is added to a unit vial of lyophilized or liquid pediatric multivitamin solution. The composition of multivitamin pediatric solution is

    ______________________________________                                         2,300      IU          vitamin A                                               400        IU          vitamin D                                               7          IU          vitamin E                                               0.2        mg          vitamin K.sub.1                                         17         mg          niacinamide                                             1.4        mg          riboflavin                                              1.2        mg          thiamin                                                 1.0        mg          pyridoxine                                              5.0        mg          pantothenic acid                                        80         mg          ascorbic acid                                           20         mcg         biotin                                                  1.0        mcg         vitamin B.sub.12                                        140.0      mcg         folic acid.                                             ______________________________________                                    

EXAMPLE 15 (Neonatal)

Three grams of fumaric acid disodium salt is dissolved in 900 mL water for injection and

    ______________________________________                                         0.032   g         copper chloride (4H.sub.2 O)                                 0.25    g         zinc chloride                                                0.014   g         manganese chloride (4H.sub.2 O) and                          0.61    mg        chromium chloride (6H.sub.2 O)                               ______________________________________                                    

are added and dissolved. The solution is q.s. to 1 liter and 5 mL of this mixture containing

    ______________________________________                                         0.06       mg            copper                                                0.6        mg            zinc                                                  0.02       mg            manganese                                             0.6        mcg           chromium                                              ______________________________________                                    

is added to a unit vial of lyophilized or liquid multivitamin containing the following vitamins:

    ______________________________________                                         1,400      IU          vitamin A                                               200        IU          vitamin D                                               4          IU          vitamin E                                               0.1        mg          vitamin K.sub.1                                         10         mg          niacinamide                                             0.8        mg          riboflavin                                              0.7        mg          thiamin                                                 0.6        mg          pyridoxine                                              3.0        mg          pantothenic acid                                        50         mg          vitamin C                                               12         mcg         biotin                                                  0.6        mcg         vitamin B.sub.12                                        90.0       mcg         folic acid.                                             ______________________________________                                    

EXAMPLE 16 (Adult)

    ______________________________________                                         0.536    g        copper chloride (2H.sub.2 O)                                 1.26     g        zinc chloride                                                0.144    g        manganese chloride (4H.sub.2 O)                              10.25    mg       chromium chloride (6H.sub.2 O)                               ______________________________________                                    

are dissolved in 900 mL water for injection. The solution is adjusted to pH 2 with hydrochloric acid and the volume is brought to 1 liter.

5 mL of this mixture containing

    ______________________________________                                                1.0 mg           copper                                                        3.0 mg           zinc                                                          0.2 mg           manganese                                                     10  mcg          chromium                                               ______________________________________                                    

is added to a unit vial of lyophilized or liquid multivitamins containing the following vitamins:

    ______________________________________                                         3,300    IU         vitamin A                                                  200      IU         vitamin D                                                  10       IU         vitamin E                                                  0.15     mg         vitamin K.sub.1                                            6.0      mg         thiamin                                                    3.6      mg         riboflavin                                                 6.0      mg         pyridoxine                                                 40       mg         niacinamide                                                60       mcg        biotin                                                     5.0      mcg        vitamin B.sub.12                                           15.0     mg         pantothenic acid                                           600      mcg        folic acid                                                 200      mg         ascorbic acid                                              0.75%    w/v        fumaric acid disodium salt                                 0.3      mg         iron peptonate                                             1.0      mg         disodium edetate.                                          ______________________________________                                    

EXAMPLE 17 (Pediatric)

Five grams of maleamic acid monosodium salt is dissolved in 900 mL water for injection and

    ______________________________________                                         0.161   g         copper chloride (2H.sub.2 O)                                 0.63    g         zinc chloride                                                0.072   g         manganese chloride (4H.sub.2 O) and                          2.05    mg        chromium chloride (6H.sub.2 O)                               ______________________________________                                    

are added and dissolved. The solution is brought to 1 liter.

Five mL of this mixture containing

    ______________________________________                                                0.3 mg           copper                                                        1.5 mg           zinc                                                          0.1 mg           manganese                                                     2   mcg          chromium                                               ______________________________________                                    

is added to a unit vial of lyophilized or liquid pediatric multivitamin solution. The composition of multivitamin pediatric solution is

    ______________________________________                                         2,300      IU          vitamin A                                               400        IU          vitamin D                                               7          IU          vitamin E                                               0.2        mg          vitamin K.sub.1                                         17         mg          niacinamide                                             1.4        mg          riboflavin                                              1.2        mg          thiamin                                                 1.0        mg          pyridoxine                                              5.0        mg          pantothenic acid                                        80         mg          ascorbic acid                                           20         mcg         biotin                                                  1.0        mcg         vitamin B.sub.12                                        140.0      mcg         folic acid.                                             ______________________________________                                    

EXAMPLE 18 (Neonatal)

2.5 grams of maleamic acid monosodium salt is dissolved in 900 mL water for injection and

    ______________________________________                                         0.032   g         copper chloride (4H.sub.2 O)                                 0.25    g         zinc chloride                                                0.014   g         manganese chloride (4H.sub.2 O) and                          0.61    mg        chromium chloride (6H.sub.2 O)                               ______________________________________                                    

are added and dissolved. The solution is q.s. to 1 liter and 5 mL of this mixture containing

    ______________________________________                                         0.06       mg            copper                                                0.6        mg            zinc                                                  0.02       mg            manganese                                             0.6        mcg           chromium                                              ______________________________________                                    

is added to a unit vial of lyophilized or liquid multivitamin containing the following vitamins:

    ______________________________________                                         1,400      IU          vitamin A                                               200        IU          vitamin D                                               4          IU          vitamin E                                               0.1        mg          vitamin K.sub.1                                         10         mg          niacinamide                                             0.8        mg          riboflavin                                              0.7        mg          thiamin                                                 0.6        mg          pyridoxine                                              3.0        mg          pantothenic acid                                        50         mg          vitamin C                                               12         mcg         biotin                                                  0.6        mcg         vitamin B.sub.12                                        90.0       mcg         folic acid.                                             ______________________________________                                    

EXAMPLE 19 (Adult)

    ______________________________________                                         0.536    g         copper chloride (2H.sub.2 O)                                1.26     g         zinc chloride                                               0.144    g         manganese chloride (4H.sub.2 O)                             10.25    mg        chromium chloride (6H.sub.2 O)                              ______________________________________                                    

are dissolved in 900 mL water for injection. The solution is adjusted to pH 2 with hydrochloric acid and the volume is brought to 1 liter.

5 mL of this mixture containing

    ______________________________________                                         1.0        mg           copper                                                 3.0        mg           zinc                                                   0.2        mg           manganese                                              10         mcg          chromium                                               ______________________________________                                    

is added to a unit vial of lyophilized or liquid multivitamins containing the following vitamins:

    ______________________________________                                         3,300      IU          vitamin A                                               200        IU          vitamin D                                               10         IU          vitamin E                                               0.15       mg          vitamin K.sub.1                                         6.0        mg          thiamin                                                 3.6        mg          riboflavin                                              6.0        mg          pyridoxine                                              40         mg          niacinamide                                             60         mcg         biotin                                                  5.0        mcg         vitamin B.sub.12                                        15.0       mg          pantothenic acid                                        600        mcg         folic acid                                              200        mg          ascorbic acid                                           1%         w/v         maleamic acid                                           0.3        mg          iron peptonate                                          1.0        mg          disodium edetate.                                       ______________________________________                                    

EXAMPLE 20 (Pediatric)

Two grams of acrylamide is dissolved in 900 mL water for injection and

    ______________________________________                                         0.161   g         copper chloride (2H.sub.2 O)                                 0.63    g         zinc chloride                                                0.072   g         manganese chloride (4H.sub.2 O) and                          2.05    mg        chromium chloride (6H.sub.2 O)                               ______________________________________                                    

are added and dissolved. The solution is brought to 1 liter.

Five mL of this mixture containing

    ______________________________________                                         0.3        mg           copper                                                 1.5        mg           zinc                                                   0.1        mg           manganese                                              2          mcg          chromium                                               ______________________________________                                    

is added to a unit vial of lyophilized or liquid pediatric multivitamin solution. The composition of multivitamin pediatric solution is

    ______________________________________                                         2,300      IU          vitamin A                                               400        IU          vitamin D                                               7          IU          vitamin E                                               0.2        mg          vitamin K.sub.1                                         17         mg          niacinamide                                             1.4        mg          riboflavin                                              1.2        mg          thiamin                                                 1.0        mg          pyridoxine                                              5.0        mg          pantothenic acid                                        80         mg          ascorbic acid                                           20         mcg         biotin                                                  1.0        mcg         vitamin B.sub.12                                        140.0      mcg         folic acid.                                             ______________________________________                                    

EXAMPLE 21 (Neonatal)

Two grams of acrylamide is dissolved in 900 mL water for injection and

    ______________________________________                                         0.032   g         copper chloride (4H.sub.2 O)                                 0.25    g         zinc chloride                                                0.014   g         manganese chloride (4H.sub.2 O) and                          0.61    mg        chromium chloride (6H.sub.2 O)                               ______________________________________                                    

are added and dissolved. The solution is q.s. to 1 liter and 5 mL of this mixture containing

    ______________________________________                                         0.06       mg           copper                                                 0.6        mg           zinc                                                   0.02       mg           manganese                                              0.6        mcg          chromium                                               ______________________________________                                    

is added to a unit vial of lyophilized or liquid multivitamin containing the following vitamins:

    ______________________________________                                         1,400      IU          vitamin A                                               200        IU          vitamin D                                               4          IU          vitamin E                                               0.1        mg          vitamin K.sub.1                                         10         mg          niacinamide                                             0.8        mg          riboflavin                                              0.7        mg          thiamin                                                 0.6        mg          pyridoxine                                              3.0        mg          pantothenic acid                                        50         mg          vitamin C                                               12         mcg         biotin                                                  0.6        mcg         vitamin B.sub.12                                        90.0       mcg         folic acid.                                             ______________________________________                                    

EXAMPLE 22 (Adult)

    ______________________________________                                         0.536    g         copper chloride (2H.sub.2 O)                                1.26     g         zinc chloride                                               0.144    g         manganese chloride (4H.sub.2 O)                             10.25    mg        chromium chloride (6H.sub.2 O)                              ______________________________________                                    

are dissolved in 900 mL water for injection. The solution is adjusted to pH 2 with hydrochloric acid and the volume is brought to 1 liter.

5 mL of this mixture containing

    ______________________________________                                         1.0        mg           copper                                                 3.0        mg           zinc                                                   0.2        mg           manganese                                              10         mcg          chromium                                               ______________________________________                                    

is added to a unit vial of lyophilized or liquid multivitamins containing the following vitamins:

    ______________________________________                                         3,300     IU           vitamin A                                               200       IU           vitamin D                                               10        IU           vitamin E                                               0.15      mg           vitamin K.sub.1                                         6.0       mg           thiamin                                                 3.6       mg           riboflavin                                              6.0       mg           pyridoxine                                              40        mg           niacinamide                                             60        mcg          biotin                                                  5.0       mcg          vitamin B.sub.12                                        15.0      mg           pantothenic acid                                        600       mcg          folic acid                                              200       mg           ascorbic acid                                           0.5%      w/v          acrylamide                                              0.3       mg           iron peptonate                                          1.0       mg           disodium edetate.                                       ______________________________________                                    

Physical stability data of a multivitamin formulation containing the vitamins of Table I in the presence of trace elements of Table II are shown in Table IV and Table IV A. In one set of experiments no stabilizer was used; in another set of experiments the water soluble saturated, weak organic acid stabilizers (citric, acetic, tartaric, gluconic, succinic, lactic, oxalic acids) were used; in the third set of experiments, maleic acid was used as the stabilizer; and in the fourth set of experiments acrylic acid was used as the stabilizer.

                                      TABLE IV                                     __________________________________________________________________________     Physical Stability                                                                             Saturated Weak                                                                          Maleic Acid                                                                             Acrylic Acid                                 Time   No Stabilizer                                                                           Organic Acids                                                                           Stabilizer                                                                              Stabilizer                                   __________________________________________________________________________     Initial                                                                               Turbid   Turbid   Clear    Clear                                        (15 seconds)                                                                          Severe darkening                                                                        Severe darkening                                                                        Very slight color                                                                       Light color                                                           change                                                2 hours                                                                               Slight precipita-                                                                       Slight precipita-                                                                       Clear, no precipi-                                                                      Clear, no precipi-                           Room temp.                                                                            tion     tion     tate. No further                                                                        tate. Light color                                   Severe darkening                                                                        Severe darkening                                                                        color change                                          4 hours                                                                               Moderate precipi-                                                                       Moderate precipi-                                                                       Clear, no precipi-                                                                      Clear, no color                              Room temp.                                                                            tation   tation   tate. No further                                                                        change. No                                          Severe darkening                                                                        Severe darkening                                                                        color change                                                                            precipitate                                  8 hours                                                                               Heavy reddish                                                                           Heavy reddish                                                                           Clear, no precipi-                                                                      Clear, no color                              Room temp.                                                                            brown precipitate                                                                       brown precipitate                                                                       tate. No further                                                                        change. No                                          Severe darkening                                                                        Severe darkening                                                                        color change                                                                            precipitate                                  24 hours                                                                              Heavy reddish                                                                           Heavy reddish                                                                           Clear, no precipi-                                                                      Clear, no color                              Room temp.                                                                            brown precipitate                                                                       brown precipitate                                                                       tate. Slight                                                                            change. No                                          Severe darkening                                                                        Severe darkening                                                                        color change from                                                                       precipitate                                                           original                                              24 hours                                                                              Heavy reddish                                                                           Heavy reddish                                                                           Clear, no precipi-                                                                      Clear, no color                              Refrigerated                                                                          brown precipitate                                                                       brown precipitate                                                                       tate. No color                                                                          change. No                                          Severe darkening                                                                        Severe darkening                                                                        change from                                                                             precipitate                                                           original                                              __________________________________________________________________________

Table V shows results of chemical stability tests conducted on vitamin C, vitamin B₁, folic acid, and vitamin B₁₂ contained in a multivitamin formulation according to Table I in the presence of the trace elements of Table II. In one set of experiments the unsaturated water soluble acid stabilizer was used, while in another set of experiments the stabilizer was omitted. The remainder of the vitamins of Table I, namely, niacinamide, vitamin B₆, vitamin B₂, biotin, vitamin K, pantothenic acid, and vitamins A, D and E were found to be relatively stable in the presence of the trace elements without the presence of stabilizers.

                  TABLE V                                                          ______________________________________                                         Chemical Stability                                                                           No Stabilizer                                                                           Stabilizer                                              ______________________________________                                         Vitamin C % Loss                                                               2 hrs. RT       14         4                                                   4 hrs. RT       23         5                                                   6 hrs. RT       30         5                                                   8 hrs. RT       40         5                                                   24 hrs. RT      93         12                                                  24 hrs. Refrig. 61         5                                                   Vitamin B.sub.1 % Loss                                                         2 hrs. RT        6         0                                                   4 hrs. RT       14         2                                                   6 hrs. RT        8         7                                                   8 hrs. RT       15         4                                                   24 hrs. RT      16         3                                                   24 hrs. Refrig. 11         1                                                   Folic Acid % Loss                                                              2 hrs. RT        9         3                                                   4 hrs. RT       10         3                                                   6 hrs. RT       --         2                                                   8 hrs. RT       --         5                                                   24 hrs. RT      43         2                                                   24 hrs. Refrig. 38         0                                                   Vitamin B.sub.12 % Loss                                                        2 hrs. RT       --         --                                                  4 hrs. RT       66         1                                                   6 hrs. RT       --         --                                                  8 hrs. RT       100        0                                                   24 hrs. RT      100        7                                                   24 hrs. Refrig. --         --                                                  ______________________________________                                    

The preceding specific embodiments are illustrative of the practice of the invention. It is to be understood, however, that other expedients known to those skilled in the art or disclosed herein, may be employed without departing from the spirit of the invention or the scope of the appended claims. 

What is claimed is:
 1. A stable aqueous multivitamin/trace elements preparation for parenteral administration comprising per milliliter of aqueous solution at least two vitamins selected from the group consisting of:

    ______________________________________                                         230-10,000 IU      Vitamin A,                                                  0.05-45.0 mg       Vitamin B.sub.1,                                            0.07-10.0 mg       Vitamin B.sub.2,                                            0.04-12.0 mg       Vitamin B.sub.6,                                            4-1,000 mg         Vitamin C,                                                  44-1,000 IU        Vitamin D,                                                  0.66-10 IU         Vitamin E,                                                  0.25-100 mg        Niacinamide,                                                0.3-25 mg          Pantothenic Acid,                                           0.04-1.0 mg        Vitamin K,                                                  10-100 mcg         Biotin,                                                     5-800 mcg          Folic Acid and                                              0.04-10 mcg        Vitamin B.sub.12 ;                                          ______________________________________                                    

20 mcg-2.8 mg of the trace element Copper; at least one trace element selected from the group consisting of:

    ______________________________________                                          100 mcg-10 mg      Zinc                                                         2 mcg-2.5 mg      Manganese and                                              0.14 mcg-20 mcg     Chromium;                                                  ______________________________________                                    

and about 0.5 to 5.0% w/v of a stabilizer selected from the group consisting of: acrylic acid and a water soluble salt thereof.
 2. A stable aqueous multivitamin/trace elements preparation for parenteral administration comprising per milliliter of aqueous solution at least two vitamins selected from the group consisting of:

    ______________________________________                                         3,300-5,000 IU     Vitamin A,                                                  3.0-6.0 mg         Vitamin B.sub.1,                                            3.0-6.0 mg         Vitamin B.sub.2,                                            4.0-6.0 mg         Vitamin B.sub.6,                                            100-200 mg         Vitamin C,                                                  200-400 IU         Vitamin D,                                                  5-10 IU            Vitamin E,                                                  40-60 mg           Niacinamide,                                                10-15 mg           Pantothenic Acid,                                           0.10-0.5 mg        Vitamin K,                                                  25-60 mcg          Biotin,                                                     400-600 mcg        Folic Acid and                                              2-5 mcg            Vitamin B.sub.12 ;                                          ______________________________________                                    

0.4-1.5 mg of the trace element Copper; at least one trace element selected from the group consisting of:

    ______________________________________                                           3-6 mg            Zinc                                                       0.15-0.80 mg        Manganese and                                                10-15 mcg         Chromium;                                                  ______________________________________                                    

and about 0.5 to 5.0% w/v of a stabilizer selected from the group consisting of: acrylic acid and a water soluble salt thereof.
 3. A stable aqueous multivitamin/trace elements preparation for parenteral administration comprising per milliliter of aqueous solution at least two vitamins selected from the group consisting of:

    ______________________________________                                         0.05-45.0 mg        Vitamin B.sub.1,                                           0.07-10.0 mg        Vitamin B.sub.2,                                           4-1,000 mg          Vitamin C and                                              5-800 mcg           Folic Acid,                                                ______________________________________                                    

20 mcg-2.8 mg of the trace element Copper; at least one trace element selected from the group consisting of:

    ______________________________________                                         100 mcg-10 mg       Zinc                                                       2 mcg-2.5 mg        Manganese and                                              0.14 mcg-20 mcg     Chromium;                                                  ______________________________________                                    

and about 0.5 to 5.0% w/v of a stabilizer selected from the group consisting of: acrylic acid and a water soluble salt thereof.
 4. A stable aqueous multivitamin/trace elements preparation for parenteral administration comprising per milliliter of aqueous solution at least two vitamins selected from the group consisting of:

    ______________________________________                                         3.0-6.0 mg          Vitamin B.sub.1,                                           3.0-6.0 mg          Vitamin B.sub.2,                                           100-200 mg          Vitamin C and                                              400-600 mcg         Folic Acid;                                                ______________________________________                                    

0.4-1.5 mg of the trace element Copper; at least one trace element selected from the group consisting of:

    ______________________________________                                         3-6 mg              Zinc                                                       0.15-0.80 mg        Manganese and                                              10-15 mcg           Chromium;                                                  ______________________________________                                    

and about 0.5 to 5.0% w/v of a stabilizer selected from the group consisting of: acrylic acid and a water soluble salt thereof.
 5. A stable aqueous multivitamin/trace elements preparation for parenteral administration comprising per milliliter of aqueous solution at least two vitamins selected from the group consisting of:

    ______________________________________                                         0.05-45.0 mg        Vitamin B.sub.1,                                           4-1,000 mg          Vitamin C,                                                 5-800 mcg           Folic Acid and                                             0.04-10 mcg         Vitamin B.sub.12 ;                                         ______________________________________                                    

20 mcg-2.8 mg of the trace element Copper; at least one trace element selected from the group consisting of:

    ______________________________________                                         100 mcg-10 mg       Zinc                                                       2 mcg-2.5 mg        Manganese and                                              0.14 mcg-20 mcg     Chromium;                                                  ______________________________________                                    

and about 0.5 to 5.0% w/v of a stabilizer selected from the group consisting of: acrylic acid and a water soluble salt thereof.
 6. A stable aqueous multivitamin/trace elements preparation for parenteral administration comprising per milliliter of aqueous solution at least two vitamins selected from the group consisting of:

    ______________________________________                                         3.0-6.0 mg          Vitamin B.sub.1,                                           100-200 mg          Vitamin C,                                                 400-600 mcg         Folic Acid and                                             2-5 mcg             Vitamin B.sub.12 ;                                         ______________________________________                                    

0.4-1.5 mg of the trace element Copper; at least one trace element selected from the group consisting of:

    ______________________________________                                         3-10 mg             Zinc                                                       0.15-0.80 mg        Manganese and                                              10-15 mcg           Chromium;                                                  ______________________________________                                    

and about 0.5 to 5.0% w/v of a stabilizer selected from the group consisting of: acrylic acid and a water soluble salt thereof. 